One-Food Versus Six-Food Elimination Diet Therapy for Eosinophilic Esophagitis Treatment

Eosinophilic esophagitis (EoE) is a chronic inflammation of the esophagus resulting from the buildup of eosinophils in the esophageal lining, with a pathogenesis akin to an allergic response to a food allergen exposure. Ongoing inflammation can lead to changes in the structure of the esophagus, such as strictures.

During childhood, symptoms representative of an inflammatory phenotype may include abdominal pain, nausea, and vomiting. In adolescence and adulthood, the disease may progress to a fibrostenotic phenotype, most often with symptoms of dysphasia.

Swallowed topical corticosteroids and proton pump inhibitors, as well as clinically-trialed biological therapies, have shown to be effective overall treatments but there are concerns over short- and long-term side effects of these medications.

A reliable test to identify the exact foods that trigger the inflammatory response in these patients is not yet available, but diet therapy with the exclusion of possible triggers has demonstrated effectiveness. A six-food elimination diet is often used as the initial approach, but there is some controversy around whether a less-extensive elimination diet should be the first step for treating these patients.

Six-food elimination diet

• Elimination of six most common food allergens often used to achieve histological remission, including:
  • Animal milk
  • Egg
  • Wheat
  • Soy
  • Fish and shellfish
  • Peanut and tree nuts
• Foods added back one at a time, mucosal response assessed by endoscopy with biopsy
• 70% histological response rate in prior studies but low patient acceptance

One-food elimination diet

• Elimination of only animal milk
• 30-60% remission in pediatric patients in prior studies

No previous randomized trials have compared these strategies in adults. Unknowns include:

• Is topical steroid therapy a successful option when food elimination diet is not?
• Is response to diet therapy associated with molecular improvement in esophagus (by markers measured in eosinophilic esophagitis diagnostic panel)?
• Do other biomarkers have predictive value?

Ten sites from the national Consortium of Eosinophilic Gastrointestinal Disease Researchers, including Children’s Hospital Colorado, conducted a multi-center, randomized, open label trial. Study goals included:

• Compare efficacy of one-food elimination diet with six-food elimination diet on clinical, histological endpoints in adults with eosinophilic esophagitis
• Assess association of biomarkers with response to diet
• Assess effectiveness of steroid therapy for non-responders of six-food elimination diet

Researchers Glenn Furuta, MD, and Paul Menard-Katcher, MD, hypothesized the six-food elimination diet would achieve superior histological remission.

Randomized trial of one-food or six-food elimination diet in adults with eosinophilic esophagitis

The study population included adult patients, 18- to 60-years-old, with active, symptomatic eosinophilic esophagitis. They were randomly assigned to a six-week, one-food elimination diet or a six-food elimination diet.

Data collection

• At baseline and end of Phase 1:
  • Whole blood for T cells assessment
    • Analyzed for markers of activation, cytokine production ex vivo
  • Serum for milk-specific immunoglobulins assessment
  • Biopsies for transcriptome analysis with the EDP
• At baseline
  • Skin prick testing for eliminated food allergens
    • Negative prick tests to cows milk underwent milk patch testing

Primary endpoint

Proportion of patients with histological remission (peak esophageal count <15 eosinophils per high-power field).

Secondary endpoints

• Proportion of complete histological remission (peak count ≤1 eosinophils per high-power field)
• Proportion of partial remission (peak counts ≤10 and ≤6 eosinophils per high-power field)
• Changes from baseline in peak eosinophil count
• Data from:
  • Eosinophilic Esophagitis Histology Scoring System (EoEHSS)
  • Eosinophilic Esophagitis Endoscopic Reference Score (EREFS)
  • Eosinophilic Esophagitis Activity Index (EEsAI)
  • Adult Eosinophilic Esophagitis Quality-of-Life and Patient Reported Outcome Measurement Information System Global Health questionnaires

Prior to participating, all participants received standardized instructions following the elimination diets were created by registered dietitians with expertise in food elimination therapies

Phase 1 study

Participants followed their assigned one-food or six-food elimination diet for six weeks. Histological response was assessed by biopsy after therapy. Those who met the primary endpoint completed the study at Phase 1.

Phase 2 study

Those who did not respond to the one-food elimination diet could choose to continue to six-food elimination diet. Participants who did not respond to six-food elimination diet could continue by using swallowed topical fluticasone propionate 880 μg twice per day (with unrestricted diet). The histological response was assessed by biopsy after six weeks of therapym, and histological remission was assessed as a secondary endpoint after a patient switched therapy. Analyses of efficacy and safety was performed in intention-to-treat population.

Histological remission of eosinophilic esophagitis similar between diet groups

Enrollment period was May 2016 to March 2019, and participants included:

• 143 patients screened
• 129 eligible, randomly assigned to diet group (intent-to-treat population)
• 67 assigned to 1-food elimination diet
• 62 assigned to 6-food elimination diet
• 125 completed Phase 1

Demographics

• 37 years mean age
• 70 (54%) men
• 59 (46%) women
• 124 (96%) white
• Peak esophageal eosinophil count only significant difference in demographic baseline characteristics between groups (higher in one-food elimination diet)

Key findings

• Percent of intent-to-treat population who achieved histological remission at 6 weeks:
  • 40% in 6-food elimination diet group
  • 34% in 1-food elimination diet group

Other Phase 1 findings

• No significant difference between the groups at stricter thresholds for partial remission
• Six-food elimination group had significantly higher percentage of complete remission
• Both groups experienced decreases in peak eosinophil counts
• No significant difference in mean changes from baseline scores for EoEHSS, EREFS
• Minimal changes in quality-of-life scores, similar between groups
• Neither group recorded adverse events in >5% of patients

Phase 2 findings

• 21 patients with no histological response to one-food elimination diet moved to six-food elimination diet
  • 9 (43%) reached histological remission
  • 6 (29%) had complete remission
• 11 patients with no histological response to six-food elimination diet moved to fluticasone propionate
  • 9 (82%) reached histological remission
  • 6 (55%) had complete remission
• Significant decrease from start of Phase 2 to end of treatment in
  • EoEHSS, EREFS scores
  • Peak eosinophil count

Additional findings

• Adherence to diet was similar among both groups
• Post-treatment transcriptomes qualitatively similar in both diet groups
• A distinct bidirectional change was detected in expression of 75 genes in treatment responders, indicating normalization of gene expression, compared with a change in four genes in treatment non-responders

Results from baseline data analysis include:

• Baseline serum concentrations of milk-specific IgG4 associated with response to one-food elimination diet
  • 43% non-responders to one-food elimination diet who moved to six-food elimination diet had a histological response
  • 82% of non-responders to six-food elimination diet who moved to topical swallowed steroid therapy a histological response.
• Baseline skin prick tests to milk – positive or negative – not associated with histological response in one-food elimination diet group
• Baseline skin prick tests to eggs associated with histological response in six-food diet elimination group
  • 70% with positive egg skin prick test in remission
  • 27% with negative egg skin prick test in remission

One-food elimination therapy for eosinophilic esophagitis is an acceptable initial approach

This is the first study to evaluate transcriptome response to elimination diets in adults. Findings demonstrate diet therapy has a profound effect on reversing the pathobiology of eosinophilic esophagitis.

• Both diets had similar efficacy in achieving histological remission, improving multiple metrics of response
• Serum IgG4 concentrations to major cow’s milk proteins may be a potential marker for milk reactivity in some patients.
• Six-food elimination diet patients had efficacy in just less than half of one-food non-responders

In addition, few studies have examined a change from dietary therapy to topical steroids/ Data from this study data supports using this strategy in adults.

• Steroids had efficacy in most six-food elimination diet non-responders

Study authors concluded the less restrictive, one-food elimination diet of animal milk is an acceptable initial approach for patients with eosinophilic esophagitis interested in empirical diet therapy.